Before the start I would like to thank all the people who supported the project at LinkedIn by your “likes”, by starting to follow our company and by sharing the link with your network. Thank you very much! This was really encouraging! I generally think that we need more science on LinkedIn. It also occurred to me that writing short popular science articles could be a good way for PhD students to tell the world some exciting stories and market themselves as potential future employees. Together we could make science much more visible on LinkedIn!

In the previous post I discussed the “when” question - when during the process of drug discovery do we need structural biology. Here I will discuss another question, which often needs to be answered before the start of a drug discovery project and this time it is a “what“ question. Assuming we have a target, what strategy do we need to follow at the start of the project? The answer depends on the basic information at hand. On the image you can see what type of information I mean - it is the structure of course:

1- the 3-dimensional structure of the protein target

2- the structure of a ligand

The general definition of “a ligand” refers to a molecule, most commonly a small molecule, that after binding to the target protein at a particular site can modulate the protein function. The binding site could be an active site (substrate binding site) if the target is an enzyme, or it could be a co-factor binding site, an allosteric site or, for example, a protein-protein interaction site. 

Looking again at the image, we see four colored quadrants and inside each of them we can read about the possible actions to follow.

Blue: known protein and ligand structures – here we have all the advantages of structure-based design (SBDD), we can also do virtual screening, docking and scoring, and much more!

Green: known protein structure, unknown ligand structure – de novo design will be the starting point and after identifying the first good quality binders we can proceed with SBDD to get the method working to our advantage.

Yellow: known ligand structure, unknown protein structure – this is the case of so-called ligand-based design. Here we can run screening using, for example, a targeted compound library, build a QSAR model (quantitative structure-activity relationships, like in SARomics!), create a pharmacophore model, and if we can construct a reliable homology model of our target protein, we could even run virtual screening.

Pink: protein and ligand structures are unknown – this is probably the most time-consuming (and costly) place to be at. In my opinion it would be much more efficient to invest in determining the 3-dimensional structure of the protein target before proceeding with the project. 

I think it is obvious where we want to be at the start of a drug discovery project, i.e. in the blue quadrant! Structure-based drug design allows us to leverage all the power of a 3D structure, thereby accelerating the drug discovery project and saving substantial costs.

In our Learning Center the process of strategy choice in drug discovery is discussed in more detail. In the upcoming posts I will discuss the principles of fragment/compound screening, hit identification, hit expansion and lead generation. I will also explain what a pharmacophore model and a QSAR model are.

Follow us on LinkedIn if you haven’t done that yet and stay tuned!